Most human cancers have abnormal numbers of chromosomes, known as aneuploidy. However, the causes of aneuploidy and its role in tumor development remain poorly understood. The mitotic checkpoint is a surveillance mechanism that prevents missegregation of chromosomes by delaying anaphase onset until all kinetochores have attached to the mitotic spindle. In certain human cancers with aneuploidy, genetic or epigenetic mutations have been identified in the mitotic checkpoint gene BubR1. During the previous funding period, we have shown that mutant mice with low levels of BubR1 undergo frequent chromosome missegregation and develop severe aneuploidy. These mice were more susceptible to carcinogen-induced tumorigenesis and, unexpectedly, developed a variety of progeroid features at young ages, suggesting that BubR1 prevents both cancer and aging. The recent discovery of biallelic BubR1 mutations in patients with mosaic variegated aneuploidy (MVA) syndrome, a recessive disorder characterized by aneuploidy, tumor susceptibility and progeroid features, further supports this idea. The overall objective of the current proposal is to understand the mechanisms by which BubR1 governs aging and cancer. Preliminary studies show that the senescence response genes p53, p21, p19 and p16 are induced when BubR1 levels decline and that the Mek-Erk signaling pathway plays a role in this induction. Using p16 knockout mice, we show that loss of this tumor suppressor accelerates lung tumorigenesis and prevents development of a subset of age-related disorders in BubR1 hypomorphic mice. In aim one, we propose to use p53, p19 and p21 knockout mice to dissect the role of the p53 pathway in BubR1-mediated cancer and aging. In aim 2, we will use BubR1 transgenic mice to determine whether intervention in the natural decline of BubRt with age prevents tumorigenesis and aging-related disorders. In aim three we will use a series of BubR1 mutant transgenes to determine which functional domains of the protein are required for suppression of cancer and aging. We will also establish whether MVA syndrome is due to impaired BubR1 kinase activity. The information gained from these studies will significantly contribute to our understanding of the molecular genetic basis of cancer and aging. Knowledge gained from these efforts could be exploited to devise novel strategies for treatment of these interrelated disorders. [unreadable] [unreadable] [unreadable]